The present invention relates to a crystallization method of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine N-carboxylic anhydride (hereinafter referred to sometimes as compound (1)) represented by the formula (1): 
in the formula, all configurations of asymmetric carbon atoms are (S) configurations, which is a common intermediate for a group of compounds which inhibit angiotensin-converting enzyme (ACE) to express a potent antihypertensive action among the therapeutic drugs for hypertension which are on the market today.
The compound (1) can be obtained by reacting N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine (hereinafter referred to sometimes as compound (2)) represented by the formula (2): 
in the formula, all configurations of asymmetric carbon atoms are (S) configurations, with N,Nxe2x80x2-carbonyldiimidazole or phosgene. The known mode of use of the above compound (1) includes the mode in which the compound (1) is not isolated from the above-mentioned reaction solution and is directly submitted to the subsequent reaction (JP-A-57-175152, U.S. Pat. No. 5,359,086) and the mode in which the above reaction mixture is distilled under reduced pressure to remove the solvent and concentrated to dryness, the dried solid is crushed, and the resulting white powder is put to use (Reference Example in JP-B-05-41159).
These conventional modes of use of the compound (1) have several drawbacks for commercial exploitation. For example, in the mode of use in which the reaction solution is directly submitted to the subsequent reaction, the reaction solvent species which can be used in the subsequent reaction is limited, unless a solvent exchange procedure is interposed, to the solvent species used in the N-carboxylic anhydride-forming reaction (hereinafter referred to as NCA forming reaction) or to a mixed solvent containing the solvent used in the NCA forming reaction. Furthermore, since the transfer and storage in a form of a solution is required, this mode of use has the disadvantage of inconvenience in the handling of this versatile intermediate compound.
Further, it is known from JP-B-05-41159 that compound (1) can be obtained in a powdery form but because the powder is acquired by concentrating to dryness the solution following the NCA forming reaction, the concomitant impurity is not removed and this procedure is not easy to follow on a commercial scale.
While the inventors of the present invention studied on the course of crystallization of the compound (1), it was found that in the crystallization of the compound (1) on a commercial scale, an oil formation and scaling tend to occur with high frequency so that it is difficult to effect stable crystallization on a commercial scale. It was also found difficult to obtain crystals of high purity and good powder characteristics.
As the result of an intensive investigation for overcoming the above disadvantages, the inventors of the present invention discovered a crystallization method by which crystals of the compound (1) can be obtained in a stable manner with good workability avoiding an oil formation and scaling and with a large mean crystal particle diameter and good powder characteristics and which can be carried into practice on a commercial scale, and have ultimately developed the present invention.
The first aspect of the present invention, therefore, is concerned with a crystallization method of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine N-carboxylic anhydride
which comprises mixing a solution of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine N-carboxylic anhydride in a good solvent with an aliphatic hydrocarbon solvent to crystallize said N-carboxylic anhydride,
the solution of said N-carboxylic anhydride in the good solvent being added to the aliphatic hydrocarbon solvent to thereby effect crystallization, while inhibiting an oil formation and scaling of said N-carboxylic anhydride.
The second aspect of the present invention, therefore, is concerned with a crystallization method of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine N-carboxylic anhydride
which comprises adding an aliphatic hydrocarbon solvent to a solution of N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanine N-carboxylic anhydride in a good solvent to crystallize said N-carboxilic anhydride,
the aliphatic hydrocarbon solvent being added sequentially over not less than xc2xc of an hour and at a temperature of not higher than 60xc2x0 C. to thereby inhibit an oil formation and scaling of said N-carboxylic anhydride.
The present invention is now described in detail.